Indolosteroids (6,12a-dimethylindeno-(4,5c)-carbazoles) and process therefor

ABSTRACT

Indolosteroids having the following formulas are disclosed   These compounds are useful as an adjunct in skin grafts.

United States Patent [191 Sircar et al.

[ INDOLOSTEROIDS (6, l 2A-DIMETHYLlNDENO-( 4,5C CARBAZOLES) AND PROCESSTHEREFOR [75] Inventors: Jagadish C. Sircar, Dover; Harold Zinnes,Rockaway, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: June 3, 1974 [21] Appl. No.: 475,559

OTHER PUBLICATIONS l-loi et al., J. Org. Chem. 24: 126-127 (1959).

Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. WintersAttorney, Agent, or FirmAlbert H. Graddis; Frank S. Chow l 5 7 ABSTRACTlndolosteroids having the following formulas are disclosed [451 Jul1,1975

These compounds are useful as an adjunct in skin grafts.

6 Claims, No Drawings 1 2 INDOLOSTEROIDS Referring to the above scheme,9-methyl-4-keto- (6,12A-DIMETHYLINDENO-(4,5C)-CARBAZOLES)l.2,3,4-tetrahydrocarbazole III is reacted with vinylli- AND PROCESSTHEREFOR thium in a solvent such as tetrahydrofuran to give IV.

The present invention relates to indolosteroids. More This is reactedwith 2-methylcyclopentanedione using specifically the present inventionrelates to 6,12a-dime- 5 a strong basic catalyst such asbenzyltrimethylamthylindeno[4,5cl-carbazoles of the formulas: moniumhydroxide available commercially as Triton B 3 (J, T. Baker Co., EastmanKodak, etc.) to give a mix- I OH ture of V and VI, the latter being thepredominant product. Both V and VI undergo facile dehydration in I 10the presence of acids such as hydrochloric acid or p-toluene-sulfonicacid to form VII. Reduction with a complex metal hydride such as sodiumborohydride of VII gives the alcohol VII which is converted to compoundI by stirring with Raney Nickel catalyst in a sol- 5 vent such astetrahydrofuran. Compound II is obtained by passing a stream of oxygenthrough a solution of VII in a solvent such as a mixture of alcohol andchloroform.

The starting compound III is prepared as described 11 20 by H. J. Teuberand D. Cornelius, Ann. Chem. 671; 1 127 (1964). Broadly speaking, theabove compounds are prepared The compounds of the invention are usefulas adjunct according to the followingreaction scheme: agents in skingraft therapy. For example, they exhibit CH uHU the property to prolongthe survival of'allografts in laboratory animals such as mice. Thusfft'an i.p". dose of mg/kg to 100 mg/kg' they prolong the life span ofallografts in mice. p a

They are indicated as an adjunct in skin graft therapy to suppress hostrejection of the graft within the above dose range. This dose canbe'varied depending upon the condition of the host being treated. 4

These compounds are administered subcutaneously or intramuscularly 'i'ndosage forms suitable for such ad ministration. For example, they arecombined with a vehicle such as a peanut oil, sesame oil and cornpounded with dosageforms by known pharmaceutical technology.

in order to illustrate further the practice of the pr'esf e'ntinvention, the following examples are included. T

EXAMPLE 1 (Znon 4-Hydroxy-9-methyl-4-vinyl-1,2,3 ,4- tetrahydrocarbazolev A suspension of 67 g (0.33 mol) of 4-keto-9-methyl-1,2,3,4-tetrahydrocarbazole in 1700 ml oftetrahydrofuran was cooled tol0 and 1.0 mol (as a 2.9 molar solution in tetrahydrofuran) ofvinyllithium was added over a 75 min period. The reaction mixture wasallowed to slowly warm up to room temperature, stirred for 2 hr,decomposed with ice-water, and extracted with dichloromethane. Thedichloromethane solution was concentrated to a small volume (not todryness) and an oil separated from solution. The upper solvent layer wasdecanted from the oil and the latter was triterated with ether to give60 g of product, mp 91-95 dec, which was of sufficient purity for use asan intermediate for further reactions. A portion was dissolved intetrahydrofuran and petroleum ether was added till crystals separated.The first crop (mp 9093) was fil- 4 ture of 500ml of xylen'e'and 11:50'r' rilof tert-butanol was added 28.1 (0.25, mol of??? metliylcyCIoPentan l,3- dione. The mixture was stirred arroom temperaturefor 15 minutes, 10.8fml of 40% methan'olic Triton B was added, and itwas refluxed under a nitrogen atmos'phere for 3 hr. using a Dean-Starkseparator toremove the water which formed during the reaction. Thereaction mixture was filtered away from insoluble unre'acted 2methyl-cyclopentaml ,3-dione and the filtrate was washed successivelywith 5% potassium hydroxide solution, aqueous sodium chloride solution,and water; The dried (Na SO organic layer was concentrated to a volumeof about 200 ml and diluted with 500 ml of ether. The resultingprecipitate (52 g) was collected and stirred at room temperature, undernitrogen, for 30 min with 450 ml of dichloromethane. The insolublecomponent 3.8g) was collected and purified by dissolving in 250 ml oftetrahydrofuran, concentrating the resulting solution to 100 ml anddiluting with 100 ml of ether. The resulting crystalline product, mp175-l80dec. weighed 3.2 g.

Anal Calcd for c,,11 1 ;o,; 'c, 78.47; H, 7.21; N, 4.36. Found: c,78.15; 11:7.33; N, 4.20. W 3,450, 1,718, 1,650, 1,604 cm.

EXAMPLE 3.

terial was sufficiently purefor use as an intermediate tered off and themother liquor was concentrated to EXAMPLE 2 3,3a,4,5 ,6,11,12,l2a-Octahydro-6,12a-dimethyl-3- hydroxyindene [4,5cl-earbazol- 1(2H )-one To a solution of 56.8 g (0.25 mol) of 4-hydroxy-9-methyl-4-vinyl-1,2,3,4-tetrahydrocarbazole in a mixfor subsequentreactions. An analytical sample was obtained by redissolving a portionin dichloromethane and diluting with ether; it had mp l-l78 dec (turnedgreen at and shrank at 158).

Anal. Calcd for C H NO C, 78.47; H, 7.21; N, 4.36. Found: C, 78.32; H,7.15; N, 4.52. v 1,758,

"It is readily distinguished from the product of the previous example byits faster mobility on thin layer chromato graphy. using aluminum oxideplates with 2- butanoneheptane 3:1) the eluant. 1

Evaporation of the original xylene-ether filtrate (see previous example)and recrystallization of the residue from dichloromethane-ether gave 7.6g of additional product, mp 168-172 dec (turned green at 97).

EXAMPLE 4 4,5,6,1 l ,12,l2a-Hexahydro-6,12a-dimethylindeno-[4,5-cl-carbazol-1(2H)-one Method A A mixture of 48.0 g (0.15 mol) of2-[2-(1,2,3,4- tetrahydro-9-methylcarbazol-4-ylidene )-ethyl ]-2-methylcyclopentane-l.3-dione, 2.4 g of p-toluenesul- 5 fonic acid and1,500 ml of benzene was refluxed under a nitrogen atmosphere for 10 minduring which time the theoretical yield of water was collected in a DeanStark water separator. The reaction mixture was cooled and the darkgreen solution was decanted from a tarry residue. This solution wasdiluted with dichloromethane, washed successively with sodium carbonate,wa ter, and saturated sodium chloride solution, dried over sodiumsulfate, and evaporated to dryness. The resulting yellow solid wasrecrystallized from dichloromel5 thane-acetonitrile to give 30 g ofproduct, mp 195-197 dec.

Anal. Calcd for C H NO: C, 83.13; H, 6.98; N. 4.62. Found: C, 82.91; H,6.96; N, 4.58. v 1,738, 1,604, 1,535. AW 248 21,000 284 12,500). 330(6123001111 2.

Concentration of the mother liquor and dilution with ether gave 7.0 g ofa less pure second crop, mp 183-190 dec.

Method B.

To a mixture of 1.07 g (0.0033 mo1)of3,3a,4,5,6,11-,12,l2a-octahydro-6,12a-dimethyl-3-hydroxyindene[4,5c]-carbazol-l(2H)-oneand 60 ml of tetrahydrofuran was added 12 ml of 18% hydrochloric acid.The resulting clear solution was allowed to stand at room temperaturefor 21 hr, concentrated under reduced pressure to one-third its volume,and slowly poured into ice cold saturated sodium carbonate solution. Themixture was stirred at ice-bath temperature for min and the resultingyellow solid was collected, washed well with water and dried in vacuoover phosphorus pentoxide. This solid (1.04 g, mp 175182 dec) wasrecrystallized several times from acetonitrile to give 463 mg ofproduct, mp 193195 dec.

EXAMPLE 5 1,2,4,5 ,6,1 1,12,12a-Octahydro-6,12a-dimethyl-1-hydroxyindeno-[4,5c]-carbazole To a suspension of 10.0 g (0.033mol)of4,5,6,11,12- ,12a-hexahydro-6,l2a-dimethylindeno-[4,5-c]-carbazol-l(2H)-one in 375 ml of 95% ethanol was added 4.1 g of sodiumborohydride followed by 25 ml of water. The mixturewas stirred at roomtemperature for 20 hr, 600 ml of water was added, and it was stirred anadditional 3 hr. The resulting precipitate was col lected and dried invacuo over P 0 to give 10 g of product, mp 1791 81 dec which wassufficiently pure for use as an intermediate for subsequent reactions.Recrystallization by dissolving in tetrahydrofuran and diluting withether gave 6.9 g of material, mp 178180 dec.

Anal. Calcd for C ,H NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 82.45; H,7.47; N, 4.62. v 3,430,

1,608, 1,540, 1,535 cm. A 248 (32,400), 283 (18,200), 296 (14,000), 312(15,800), 325 (17,000)m 1 EXAMPLE 6 N CH 31,2,3,3a,6,11,12,12a-Octahydro-6,12a-dimethyl-lhydroxyindeno-[4,5cl-carbazoleA mixture of 10.0 g (0.033 m0l)of1,2,4,5,6,11,12,1-2a-octahydro-6,l2u-dimethyl-1-hydroxyindeno-[4,5c]- carbazole, 5 g of W7Raney Nickel catalyst and 350 ml of tetrahydrofuran was stirredvigorously at room temperature under a nitrogen atmosphere for 6 hr. andthen allowed to stand overnight. The catalyst was filtered off, thesolvent was evaporated, and the solid residue was triturated with etherto give 8.7 g of crystalline product, mp 217221 dec. Recrystallizationfrom dichloromethane-methanol to give 5.9 g of material, mp 220-22l dec.

Anal. Calcd for C H NO: C, 82.59; H, 7.59; N. 4.59. Found: 82.47; H.7.63; N, 4.34. v-"' 3,260, 1,582, 1,475 cm. k 242 (646,000), 268(24,000), 293 (17,600), 352 (6,000).

EXAMPLE 7 Cll l f 6,1 1,12,12a-Tetrahydro-6,12-a-dimethylindeno-[4,5-c]-carbazol- 1 (2H )-one A stream of oxygen was passed through asolution of 5.0 g (0.0165 mol) of 4,5,6.11,12,12a-hexahydro-6,12a-dimethylindeno-[4,5-c]-carbazol-l(2H)-one in a mixture of 300 mlof chloroform and 300 ml of ethanol for 48 hr. It was concentrated to avolume of about 200 ml and the resulting precipitate was collected,washed with ether, and dried to give 2.2 g of pink crystalline solid, mp230240. Recrystallization by dissolving in dichloromethane and dilutionwith acetonitrile gave 1.6 g of pink crystalline product, mp 243246 dec.Another recrystallizatoin gave an analytical sample, mp 244246 dec.

Anal. Calcd for C H NO: C, 83.69; H, 6.35; N, 4.65; Found: C, 83.65; H,6.47; N, 4.49. v 1,725, CHI-L Amar (50,800), 341 (3,800), 358 (3,800)[II/L.

We claim:

1. A member selected from the group consisting of compounds of theformula:

f I i 11 f I/J\\%I' J Ti.

VII

2. A process for the pr uC 0 0f comp n I reducingsaid compound VII witha complex metal hy cording to claim 1 which comprises reacting a comd idto b i a po nd of the formula: pound of the formula l5 CH3 I v t.

III v and reacting said compound VIII with a Raney nickel catalyst. Hwith CH2 CHLi to Obtain Compound W of the 3. A process for theproduction of compound II acmula, I cording to claim 1 which comprisestreating a compound of the formula CH=CH2 CH3 I 9 a v v i CH VIIreacting compound IV with with oxygen. 4. A compound of the formula:

. a I I to obtain compounds V and VI of the formula:

' CH r I on l i i I L K I cm ;i l V k n l r 5. A compound of theformula: CH

CH3 v 3 I VI i dehydrating said compounds V and VI to obtain a com- CH3pound of the formula: I Vt t 6. A compound of the formula:

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA:
 2. A process for the production of compound I according toclaim 1 which comprises reacting a compound of the formula
 3. A processfor the production of compound II according to claim 1 which comprisestreating a compound of the formula
 4. A compound of the formula:
 5. Acompound of the formula:
 6. A compound of the formula: